The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
Pharmaceutically active piperidine derivatives are disclosed in WO99/38514, WO99/04794 and WO00/35877.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rxc3x4le in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cysxe2x80x94Xxe2x80x94Cys (Cxe2x80x94Xxe2x80x94C, or xcex1) and Cysxe2x80x94Cys (Cxe2x80x94C, or xcex2) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The Cxe2x80x94Xxe2x80x94C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The Cxe2x80x94C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1xcex1 and 1xcex2 (MIP-1xcex1 and MIP-1xcex2).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, H1, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. H1 antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, Greiff L et al Allergy (1999) 54(11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].)

wherein:
q, s and t are, independently, 0 or 1;
n and r are, independently, 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2;
X is CH2, C(O), O, S, S(O), S(O)2 or NR37; provided that when m and p are both 1 then X is not CH2;
Y is NHR2 or OH;
T is C(O), C(S), S(O)2 or CH2;
R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl;
R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl);
R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, CR3aR3bR3c, C2-4 alkenyl {optionally substituted by aryl or heterocyclyl}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl, aryl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;
R3a is hydrogen, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl; R3b is aryl, heterocyclyl, S(O)2aryl or S(O)2heterocyclyl; and R3c is C1-6 alkyl, C1-4 haloalkyl, hydroxy, heterocyclyl(C1-4 alkyl) or aryl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl {itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)}, NR41(O)OCH2(fluoren-9-yl), C1-6 alkoxy {itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)}, C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, SCN, CN, SO3H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;
d is 0, 1 or 2;
R4, R5,R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), C3-6 alkenyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
or an N-oxide thereof; or a pharmaceutically acceptable salt thereof; or a solvate thereof;
provided that:
when m and p are both 1, n, q and r are all 0, T and X are both S(O)2, and R1 is methoxyphenyl then R3 is not propyl; when m, p, q and r are all 1, n is 0, Y is NH2, T is CO and R1X is (CH3)2N then R3 is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R1 is 3-(4-fluorobenzyl)benzimidazol-2-yl then R3 is not 4-fluorophenyl.
Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.
Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate. Another example of an addition salt is sulphate.
The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
Halogen includes fluorine, chlorine, bromine and iodine.
Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
Alkenyl group are, for example, vinyl or allyl.
Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl or camphoryl. The cycloalkyl ring is optionally fused to a benzene ring (for example forming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).
Cycloalkenyl is especially monocyclic and is, for example, cyclopentenyl or cyclohexenyl.
Aryl is preferably phenyl or naphthyl.
Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
In one aspect of the invention heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example, furyl, thienyl, 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, quinoxaline, dihydro-1-benzopyrylium (for example a coumarin or a chromone), piperidine, morpholine, pyrrole, indole, 2,3-dihydroindole, quinoline, thiazole, pyrazole, isoxazole, imidazole, pyridine, benzofuryl, benzimidazole, pyrimidine or dibenzothiophene.
In a further aspect heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), quinolinyl, isoquinolinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
An N-oxide of a compound of formula (I) is, for example, a 1-oxy-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-yl compound.
In another aspect the present- invention provides a compound of formula (Ixe2x80x2): 
wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, CO, O, S, S(O), S(O)2 or NR37; provided that when m and p are both 1 then X is not CH2; Y is NHR2 or OH; T is CO, CS, SO2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 is hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, SO2R38 or CONR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), NR41(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9COR10, CO2R11, CONR12 R13, COR14, SOdR15, SO2NR42R43, NR44SO2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38 and R45 are, independently, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both SO2, and R1 is methoxyphenyl then R3 is not propyl; when m, p, q and r are all 1, n is 0, Y is NH2, T is CO and R1X is (CH3)2N then R3 is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R1 is 3-(4-fluorobenzyl)benzimidazol-2-yl then R3 is not 4-fluorophenyl.
In an further aspect the present invention provides a compound of formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, C(O), O, S, S(O), S(O)2 or NR37; provided that when m and p are both 1 then X is not CH2; Y is NHR2 or OH; T is C(O), C(S), S(O)2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)), NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl) or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both S(O)2, and R1 is methoxyphenyl then R3 is not propyl; when m, p, q and r are all 1, n is 0, Y is NH2, T is CO and R1X is (CH3)2N then R3 is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R1 is 3-(4-fluorobenzyl)benzimidazol-2-yl then R3 is not 4-fluorophenyl.
In another aspect the variables m and p are such that m+p is 0, 1 or 2 (for example 1 or 2).
In a further aspect n is 0 or 1.
In a still farther aspect q and r are both 0.
In another aspect n, q and r are all 0.
In another aspect m, p and t are all 1.
In a further aspect s is 0.
In another aspect s is 1. In a further aspect q is 1. In a still further aspect n+r is equal to more than 1 (for example n+r is equal to 2, 3, 4 or 5).
In another aspect t+m+p is not equal to 3 (for example t+m+p is equal to 2).
In a still further aspect X is O.
In another aspect R1 is hydrogen, C1-6 alkyl, optionally substituted (as above) aryl or optionally substituted (as above) monocyclic heterocyclyl. In another aspect R1 is phenyl substituted with one or more of fluorine, chlorine, C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy).
In yet another aspect R1 is not phenyl substituted by cycloalkyl.
In a further aspect R1 is phenyl optionally substituted (for example with one, two or three) by halo (especially fluoro or chloro), C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy). In a still further aspect R1 is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
In another aspect R1 is one of the substituted phenyl groups exemplified in Method F below.
In a further aspect T is C(O), S(O)2 or CH2. In a still further aspect T is C(O). In another aspect T is S(O)2 or CH2.
In another aspect R3 is aryl or heterocyclyl either of which is optionally substituted as described above.
In a further aspect R3 is unsubstituted phenyl, mono-substituted phenyl or mono-substituted heterocyclyl, the substituents being chosen from those described above.
In a still further aspect R3 is oxo substituted heterocyclyl, said heterocyclyl optionally further substituted with one or more substituents chosen from those described above.
In another aspect R3 is a bicyclic heterocyclyl optionally substituted as described above. Bicyclic heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Bicyclic heterocyclyl is, for example, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo [3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl) or a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof
In yet another aspect R3 is: C1-6 alkyl {optionally substituted by CO2R16 or phthalimide}, C3-7 cycloalkyl {optionally substituted by oxo}, phenyl {optionally substituted by: halogen, OH, SH, C1-6 alkyl (itself optionally substituted by naphthyloxy (itself optionally substituted by halo or alkenyl) or NR17C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by CO2R18, NR19R20 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, C1-4 haloalkyl, OCF3, nitro, C3-7 cycloalkyl, NR21R22, NR23C(O)R24, CO2R25, C(O)NR26R27, S(O)2R28, phenyl (itself optionally substituted by NO2 or alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy, or adjacent substituents may join to form a dihydrophenanthrene moiety}, naphthyl {optionally substituted by NR29R30 or OH}, heterocyclyl {optionally substituted by halo, NO2, oxo, C1-6 alkyl (itself optionally substituted by OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or alkyl)), alkoxy, CF3, thioalkyl, C(O)R31, CO2R32, NR33C(O)R34, phenoxy, phenyl or nitrogen containing heterocyclyl;
R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R30, R31, R32, R33 and R34 are, independently, hydrogen, C1-6 alkyl or phenyl;
R28 is C1-6 alkyl; or a pharmaceutically acceptable salt thereof.
In another aspect R3 is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2(C1-4 alkyl), S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1 or 2 (preferably 2); and R46 is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl(C1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C1-4 haloalkylthio, C(O)NH2, NHS(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl) or S(O)2N(C1-4 alkyl)2.
In one aspect the variable R3 can be benzo[1,2,3]thiadiazolyl, thiophenyl or phenyl; the phenyl and thiophenyl rings being optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2(C1-4 alkyl), S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1 or 2 (preferably 2); and R46 is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl(C1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C1-4 haloalkylthio, C(O)NH2, NHS(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl) or S(O)2N(C1-4 alkyl)2.
In another aspect the variable R3 can be benzo[1,2,3]thiadiazolyl or phenyl (optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1 or 2; and R46 is C1-4 alkyl or phenyl) or C1-4 haloalkylthio.
In a still further aspect the present invention provides a compound of formula (Iaxe2x80x3): 
wherein:
T is C(O), C(S), S(O)2 or CH2;
n is 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2 (but are especially both 1);
R50 is hydrogen, cyano, S(O)2(C1-4 alkyl), S(O)2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR12xe2x80x2R13xe2x80x2, NR9xe2x80x2C(O)R10xe2x80x2, S(O)2R15xe2x80x2, S(O)2NR42R43 or NR44S(O)2R45 group);
R51 and R52 are, independently, hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;
R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
R4, R5, R6, R7, R8, R9, R9xe2x80x2, R10, R10xe2x80x2, R11, R12, R12xe2x80x2, R13, R13xe2x80x2, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or phenyl;
R15, R15xe2x80x2 and R45 are, independently, C1-6 alkyl or phenyl;
or a pharmaceutically acceptable salt thereof.
In a further aspect R50, R51 and R52 are, independently, hydrogen, halogen, (especially fluoro or chloro), C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy).
In a still further aspect the present invention provides a compound of formula (Ia): 
wherein:
T is C(O), C(S), S(O)2 or CH2;
n is 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2 (but are especially both 1);
R35 is hydrogen, cyano, S(O)2(C1-4 alkyl), S(O)2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR12xe2x80x2R13xe2x80x2, NR9xe2x80x2C(O)R10xe2x80x2, S(O)2R15xe2x80x2, S(O)2NR42R43 or NR44S(O)2R45 group);
R36 is hydrogen, halogen or C1-4 alkyl;
R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
R4, R5, R6, R7, R8, R9, R9xe2x80x2, R10, R10xe2x80x2, R11, R12, R12xe2x80x2, R13, R13xe2x80x2, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or phenyl;
R15, R15xe2x80x2 and R45 are, independently, C1-6 alkyl or phenyl;
or a pharmaceutically acceptable salt thereof.
In another aspect the present invention provides a compound of formula (Iaxe2x80x2): 
wherein:
T is CO, CS, SO2 or CH2;
n is 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2 (but are especially both 1);
R35 is hydrogen, cyano, SO2(C1-4 alkyl), SO2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one CONR12xe2x80x2R13xe2x80x2, NR9xe2x80x2COR10xe2x80x2, SO2R15xe2x80x2, SO2NR42R43 or NR44SO2R45 group);
R36 is hydrogen, halogen or C1-4 alkyl;
R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9COR10, CO2R11, CONR12R13, COR14, SO2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
R4, R5, R6, R7, R8, R9, R9xe2x80x2, R10, R10xe2x80x2, R11, R12, R12xe2x80x2, R13, R13xe2x80x2, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or phenyl; R15, R15xe2x80x2 and R45 are, independently, C1-6 alkyl or phenyl;
or a pharmaceutically acceptable salt thereof.
In a further aspect R3 is heterocyclyl (such as thienyl, isoxazolyl or indolyl, or a naphthyridinyl, an imidazopyridinyl or an isoquinolinyl) optionally substituted by oxo, halogen or C1-6 alkyl.
In yet another aspect the present invention provides a compound of formula (Ia) wherein:
T is C(O), C(S), S(O)2 or CH2;
n is 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2;
R35 is hydrogen, halogen or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR12xe2x80x2R13xe2x80x2, NR9xe2x80x2C(O)R10xe2x80x2, S(O)2R15xe2x80x2, S(O)2NR42R43 or NR44S(O)2R45 group);
R36 is hydrogen or halogen;
R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
R4, R5, R6, R7, R8, R9, R9xe2x80x2, R10, R10xe2x80x2, R11, R12, R12xe2x80x2, R13, R13xe2x80x2, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl;
R15, R15xe2x80x2 and R45 are, independently, C1-6 alkyl or aryl;
or a pharmaceutically acceptable salt thereof.
In a further aspect R35 and R36 are, independently, hydrogen, halogen, (especially fluoro or chloro), C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy). In another aspect R35 and R36 are both chlorine or both fluorine, especially 3,4 disposed on the phenyl ring to which they are attached.
In a further aspect the present invention provides a compound of formula (Ib): 
wherein T, n and R3 are as defined above.
In a still further aspect the present invention provides a compound of formula (Ic): 
wherein T, m, p and R3 are as defined above.
In another aspect the present invention provides a compound of formula (Id): 
wherein R3 is as defined above.
In yet another aspect the present invention provides a compound of formula (Ie): 
wherein R1, t, s and R3 are as defined above.
In a further aspect the present invention provides a compound of formula (If): 
wherein R1, n, t, s and R3 are as defined above.
In a still further aspect the present invention provides a compound of formula (Ig): 
wherein R1, X and R3 are as defined above.
A compound of formula (I), wherein s is 0, can be prepared by coupling a compound of formula (II): 
with a compound of formula (III): 
wherein L is a suitable leaving group, and the variables Y and T are optionally protected during the course of the reaction by standard protecting groups known in the art and deprotected in a separate step or during the reaction work-up. For example:
when T is carbonyl, L can be OH and the coupling can be carried out in the presence of a coupling agent (such as bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, (known as PYBROP(trademark)), oxalyl chloride, thionyl chloride or N,Nxe2x80x2-carbonyl diimidazole, or another coupling agent known to a person skilled in the art); or,
when T is sulphonyl, L can be chloro and the coupling can be carrier out in the presence of a suitable base (such as potassium carbonate) in a suitable solvent (such as acetone).
A compound of formula (I), wherein s is 1, R47 is hydrogen and T is CO, can be prepared by reacting a compound of formula (II), wherein m and p are both 1, with an aromatic isocyanate of formula with an isocyanate Oxe2x95x90Cxe2x95x90Nxe2x80x94(CH2)nxe2x80x94(CH2)rxe2x80x94R3.
A compound of formula (II) can be prepared by deprotecting a compound of formula (IV): 
for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane).
A compound of formula (IV), wherein X is O, can be prepared by reacting a compound of formula (V): 
with a compound of formula (VI): 
in the presence of NaBH(OAc)3 and acetic acid.
A compound of formula (IV), wherein X is CO or CH2, can be prepared by oxidising or reducing a compound of formula (VII): 
A compound of formula (VII) can be prepared by reacting a compound of formula (VIII): 
with a compound of formula (VI) in the presence of NaBH(OAc)3 and acetic acid. A compound of formula (VIII) can be prepared by reduction of a compound of formula (IX): 
A compound of formula (I) wherein X is NR37 can be prepared by reacting a compound of formula (X): 
with a compound of formula (XI): 
in the presence of NaBH(OAc)3 and acetic acid. A compound of formula (X) can be prepared by reacting NHR1R37 with a compound of formula (XII): 
in the presence of NaBH(OAc)3 and acetic acid and then deprotecting the piperidine nitrogen {for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane)}.
Alternatively, a compound of formula (I), wherein s, n, q and r are all 0 and T is CO, can be prepared by reacting a compound of formula (XIII): 
with an acid: R3CO2H. A compound of formula (XIII) can be prepared by deprotecting a compound of formula (XIV): 
wherein L* is BOC or a benzyl group. A compound of formula (XIV) can be prepared by performing a fluoride displacement reaction on FR1 in the presence of compound of formula (XV): 
A compound of formula (XV) can be prepared by coupling a compound of formula (XVI) with a compound of formula (XVII): 
Alternatively, a compound of formula (I) wherein s, n, q and r are all 0 and T is CO, can be prepared by performing a fluoride displacement reaction on FR1 in the presence of compound of formula (XVIII): 
provided that R47 is not hydrogen.
A compound of formula (XVIII) can be prepared by reacting a compound of formula (XIX): 
with an appropriate mixed anhydride (such as an anhydride of formula R3C(O)OC(O)(C1-6 alkyl), wherein alkyl is, for example, methyl, ethyl or iso-butyl). A compound of formula (XIX) can be prepared by deprotecting a compound of formula (XV).
Alternatively, a compound of formula (I) can be prepared by reductive ammination of a compound of formula (XX): 
with an amine of formula (XXI): 
under suitable conditions.
Further compounds of formula (I) can be prepared by adaptation of: the routes described above, methods described in the art or the Examples recited below.
Compounds of formula (V), (VI), (IX), (XI), (XII), (XVI) and (XVII) can be prepared by using or adapting methods described in the art.
In another aspect the present invention provides processes for the preparation of compounds of formula (I) (as defined above), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) and (Ig).
The intermediates of formula (II), (IV), (XIII), (XIV) and (XVII) defined herein are novel and these, and processes for their preparation, are provided as further features of the invention.
Examples of compounds of formula (Ib) are listed in Table I below.
Examples of compounds of formula (Ic) are listed in Table II below.
Examples of compounds of formula (Id) are listed in Table III below.
Examples of compounds of formula (If) are listed in Table IV below.
Examples of compounds of formula (Ig) are listed in Table V below.
The compounds of formula (I): 
wherein:
q, s and t are, independently, 0 or 1;
n and r are, independently, 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2;
X is CH2, C(O), O, S, S(O), S(O)2 or NR37;
Y is NHR2or OH;
T is C(O), C(S), S(O)2 or CH2;
R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl;
R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl);
R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, CR3aR3bR3c, C2-4 alkenyl {optionally substituted by aryl or heterocyclyl}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl, aryl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;
R3a is hydrogen, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl; R3b is aryl, heterocyclyl, S(O)2aryl or S(O)2heterocyclyl; and R3c is C1-6 alkyl, C1-4 haloalkyl, hydroxy, heterocyclyl(C1-4 alkyl) or aryl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl {itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)}, NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy {itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)}, C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, SCN, CN, SO3H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;
d is 0, 1 or 2;
R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), C3-6 alkenyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
or an N-oxide thereof; or a pharmaceutically acceptable salt thereof; or a solvate thereof; have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
In one aspect examples of these conditions are:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer""s lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter""s disease), Behxc3xa7et""s disease, Sjogren""s syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
(6) (other tissues or diseases) Alzheimer""s disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
In another aspect examples of these conditions are:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer""s lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter""s disease), Behcet""s disease, Sjogren""s syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
(6) (other tissues or diseases) Alzheimer""s disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
In a further aspect examples of these conditions are:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer""s lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter""s disease), Behcet""s disease, Sjogren""s syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
(6) (other tissues or diseases) Alzheimer""s disease, multiple sclerosis, atherosclerosis, Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
The compounds of formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, are also H1 antagonists and may be used in the treatment of allergic disorders.
The compounds of formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).
Thus, in a further aspect the present invention provides a compound of formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, which is both a modulator of chemokine receptor (especially CCR3) activity and an H1 antagonist.
According to a further feature of the invention there is provided a compound of the formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a pharmaceutically acceptable salt thereof or a solvate thereof.
According to another feature of the present invention there is provided a method for antagonising H1 in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof.
The invention also provides a compound of the formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.
In another aspect the invention provides the use of a compound of formula (I) (as defined anywhere herein), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).
In a further aspect the present invention provides the use of a compound of the formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, C(O), O, S, S(O), S(O)2 or NR37; Y is NHR2 or OH; T is C(O), C(S), S(O)2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)), NR41(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl) or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).
In another aspect the present invention provides the use of a compound of the formula (Ixe2x80x2): 
wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, CO, O, S, S(O), S(O)2 or NR37; Y is NHR2 or OH; T is CO, CS, SO2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 is hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, SO2R38 or CONR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9COR10, CO2R11, CONR12R13, COR14, SOdR15, SO2NR42R43, NR44SO2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38 and R45 are, independently, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man).
The invention further provides the use of a compound of formula (I) (as defined anywhere above), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer""s lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter""s disease), Behcet""s disease, Sjogren""s syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
(6) (other tissues or diseases) Alzheimer""s disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle;
in a warm blooded animal, such as man.
In a further aspect a compound of formula (I) (as defined anywhere above), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}.
In a still further aspect a compound of formula (I) (as defined anywhere above), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.
The invention also provides the use of a compound of formula (I) (as defined anywhere above), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection).
The present invention also provides a the use of a compound of formula (I) (as defined anywhere above), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) or an H1 mediated disease state (such as an allergic disorder) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
The present invention also provides a method of treating a sign and/or symptom of a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising H1, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkgxe2x88x921 to 100 mgkgxe2x88x921 of the compound, preferably in the range of 0.1 mgkgxe2x88x921 to 20 mgkgxe2x88x921 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (Ixe2x80x2), (Iaxe2x80x3), (Ia), (Iaxe2x80x2), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically-acceptable salt thereof (hereafter Compound X), for therapeutic or prophylactic use in humans:
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl xcex2-cyclodextrin may be used to aid formulation.
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) when given, 1H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6 (CD3SOCD3) or CDCl3 as the solvent unless otherwise stated;
(ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (EI) or fast atom bombardment (FAB); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion xe2x88x92(M+H)+;
(iii) the title and sub-titled compounds of the examples and methods were named using the AUTONOM program from Beilstein informationssysteme GmbH;
(iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, NovaPak or Ex-Terra reverse phase silica column; and
(v) the following abbreviations are used: